Developments in Pulmonary Arterial Hypertension Management

The following disclosures had been provided by speakers by the time this activity took place:
That he or she has a significant financial interest or relationship with the manufacturer of a commercial product or provider of a commercial service that could be perceived as a conflict of interest in the context of this presentation:

Gerald Simonneau, MD
Schering-Plough – Consultant
United Therapeutics – Consultant
Pfizer – Consultant
Actelion – Consultant
Encysive – Consultant

Lewis J. Rubin, MD
Actelion – Consultant, Investigator
Pfizer – Consultant, Investigator
Myogen – Consultant, Investigator
United Therapeutics – Consultant, Investigator
Schering-Plough – Consultant, Investigator

Eli Gabbay, MD
Actelion – Advisory Board
Vallerie V. McLaughlin, MD
Actelion – Speaker, Research Funds, Consultant
United Therapeutics – Speaker,
Research Funds, Consultant
Encysive – Consultant, Research Funds
Pfizer – Research Funds, Speaker
Myogen – Research Funds.

Does Current Management of PAH Affect Survival?

Data from the National Institutes of Health’s (NIH) registry shows that patients with Idiopathic Pulmonary Arterial Hypertension (IPAH) have survival curves worse than some cancers. One-, 3- and 5-year survival rates are 68%, 48% and 34% respectively (D’ Alonzo GE, et al Annal Int Med. 1991; 115:342).

“This is a horrific survival rate, “ said Vallerie McLaughlin, M.D., Director of the Hypertension Program at the University of Michigan in Ann Arbor. “This indicates the natural history of the disease and what we want to impact.”

The NIH registry and other cohort studies have demonstrated which factors adversely impact survival. These include advanced New York Heart Association (NYHA) Functional Class (FC), poor exercise endurance as measured by the 6-minute walk test (6MWT), pericardial effusions, elevated mean right atrial pressure (mRAP) and reduced cardiac index (CI). Factors that are not as strongly correlated with prognosis include elevated mean pulmonary arterial pressure (mPAP), an elevated Tei index, low peak oxygen consumption, low peak systolic and diastolic pressures during cardiopulmonary exercise testing, as well as an elevated brain natriuretic peptide (BNP) (McLaughlin V et al. Chest. 2004; 126:78s).

PAH may appear in association with other disorders, most commonly scleroderma. This is concerning since patients with scleroderma and PAH have a worse prognosis than IPAH. Conversely, when PAH is associated with congenital heart disease, they have better survival.

To describe the natural history of the disease, a sophisticated equation was developed to predict length of survival based on baseline mPAP, mRAP and cardiac index (CI) from an analysis of the NIH registry. Statistically, the mRAP is the best single predictor (D’ Alonzo GE et al Annal Int Med. 1991;115:342).

“We all think of this disease in terms of pulmonary artery pressure, but it is much more than that,” said Dr. McLaughlin. “When they get sicker it is not because their pulmonary artery pressure goes up. Cardiac output decline is what leads to worsening of the disease.”

Epoprostenol was the first drug to demonstrate an improvement in survival. In 1996, Barst and associates randomized patients with PAH who were Class III or IV to epoprostenol plus conventional treatment or only conventional treatment. At the 12-week endpoint, there were eight deaths in the conventional therapy group and none in the treatment cohort, resulting in a statistically significant improvement in survival (Barst R et al. NEJM.1996;334:296).

In terms of prognostic indicators, epoprostenol improves functional class. In a series by Dr. Olivier Sitbon and his group, and another by Dr. McLaughlin, 75% of those taking the medication improved functional class. At one-year, in both series, those in functional class I or II on medication, had a better observed survival curve when compared with those in functional class III or IV (Sitborn O et al. JACC. 2002;40:780; McLaughlin V et al. Circ. 2002;106: 1477).

“One of the messages that I take from these papers is that we want to treat people earlier and to improve functional class so they do better in terms of
mortality,” she said.

For those with scleroderma, there is not the long-term data that is available in primary PAH. However, epoprostenol does improve cardiac index, mRAP, and pulmonary vascular resistance.

“One of the reasons it has been so hard to have any other drug in a controlled trial demonstrate a mortality benefit is because we know epoprostenol works,” said Dr. McLaughlin. “If a patient in a trial is not doing well, we are quick to pull them out and start epoprostenol. The next best comparison is the composite endpoint of time-to-clinical-worsening.”

Clinical worsening is defined as the shortest time to death, starting epoprostenol, atrial septostomy or lung transplantation. There have been two placebo-controlled trials that demonstrated an improvement in time-to-clinical-worsening for bosentan versus placebo.

In the Bosentan: Randomized Trial of Endothelin Receptor Antagonist Therapy for Pulmonary Hypertension (BREATHE-1), Dr. Rubin saw only 5% of patients on bosentan and 15% of patients on conventional therapy reach the clinical worsening endpoint during the 16-week trial. At 28 weeks, 11% of patients on bosentan and 37% of conventional therapy patients reached that endpoint. Outcomes also improved in FC and 6MWT. The first placebo-controlled trial published by Channick , et al. also demonstrated an improvement in hemodynamic variables (mPAP, mRAP, PVR, CI) (Channick MD et al. Lancet.2001;358:1119; Rubin L et al. NEJM. 346;12:896).

“Another way to assess survival is to observe long-term survival and compare it with other data that is available,” said Dr. McLaughlin.

One study followed 169 patients with primary pulmonary hypertension (PPH) who were given bosentan for up to three years. Observational survival was 96%, 89% and 86% at 1, 2 and 3 years, respectively. The survival prediction, based on the equation described earlier, was 69%, 57% and 47% at the three timeframes. At each time point, first-line therapy with bosentan was improving survival compared to expectations (McLaughlin V et al. AJRCCM. 2003;167:A442).

Olivier Sitbon and his group compared a cohort of 139 FC III patients on bosentan with a cohort of 346 FC III patients taking epoprostenol. First-line bosentan therapy in FC III patients had a statistically similar survival compared to first-line epoprostenol. This was an observational study and not placebo-controlled (Sitbon O et al. AJRCCM. 2004;169:A210).

“This is yet another indication that we need to begin treatment early,” said Dr. McLaughlin. “Then we have the best chance to improve outcomes and
survival.”

Dr. Nazzareno Galie and others found a reduction in another prognostically important parameter—pericardial effusion. There was a reduction in size in those treated with bosentan compared to a worsening in the placebo group (Galie N et al. JACC. 2003;41:1386).

“Overall we are improving survival in these patients with our current medical therapies,” said Dr. McLaughlin. “We are also improving the important prognostic indicators of functional class, exercise endurance, echo parameters and hemodynamics.”

Overview of Evidence-based Algorithm for Pulmonary Hypertension

Over the last decade, new treatments for PAH brought about clinical improvement and even prolongation of life. Several treatment options are available making the selection of the best treatment for a specific patient complex and uncertain.

“Recently several evidence-based guidelines have been proposed and published,” said Gerald Simonneau, M.D., Professor and Director of the Pneu-monology Unit, Hôpital Antoine Beclere, Clamart, France. “Guidelines from The European Society of Cardiology will soon be published focusing on treatment for FC III/IV IPAH. This is the largest group for whom we have consistent data.”

“The first step in managing these patients is basic therapy, including oral anticoagulants, diuretics, oxygen and digoxin,” said Prof. Simonneau. “The second step is to perform acute vasoreactivity testing to detect the small population that responds to oral calcium antagonists.”

Using diuretics is strongly recommended, especially in those patients with edema and/or ascites, as are oral anticoagulants. Oxygen use is not as strongly recommended and digoxin’s benefit is uncertain.

Although calcium channel blockers (CCB) are not approved for IPAH, uncontrolled data indicates CCBs should only be used in patients with a fall of at least 10 mm Hg in mean pulmonary arterial pressure to less than 40 mm Hg with an increase in cardiac output when exposed to nitric oxide or prostacyclin.

Epoprostenol is approved for IPAH and PPAH associated with connective tissue disorders. It is recommended based on the results of three RCTs, two in primary PAH and another in connective tissue disorders (CTD). In addition to having been shown to improve exercise capacity, hemodynamics, and
survival, data suggests it improves long-term survival compared to standard therapies.

“Due to the complexity of administering IV epoprostenol, other prostanoid analogues have been developed,” said Prof. Simonneau. “These include iloprost via inhalation, an oral form of beraprost and subcutaneous (SQ) treprostinil.”

Treprostinil is approved for PAH in FC II/III/IV. It increases exercise capacity, improves signs and symptoms and hemodynamics in a large RCT. The main concerns are a complex delivery system and local side effects leading to high discontinuation rates.
“Oral endothelial receptor antagonists (ERA) represent a very attrac-
tive new class of drugs,” said Prof. Simonneau. “There are three drugs
currently in clinical practice.”
Bosentan is a dual ERA approved for pulmonary hypertension in FC III/IV in the U.S., but only FC III in Europe. It has been shown to improve exercise capacity, hemodynamics, FC, and time-to-clinical worsening in two RCTs.

Some long-term studies indicate bosentan may improve survival compared to standard therapy. The main side effect is an elevation in liver enzymes that resolved when the dose was lowered or discontinued.

“First- line therapy with bosentan does not adversely effect outcomes when compared to epoprostenol in IPAH FC III patients,” noted Prof. Simonneau.

Sitaxsentan and ambrisentan are ERAs in early development that have not yet been approved. Since trials are currently underway, no recommendations can be made.

Sildenafil, a phosphodiesterase-5 inhibitor is not approved for this indication. A number of uncontrolled studies have reported a favorable effect in PH while others indicated deleterious effects when combined with other vasodilators.

“So far treatment should only be considered in those with PAH who have failed or are not candidates for other therapies,” stressed Dr. Simonneau.

Although no such therapies have been approved, combination drugs with differing mechanisms of action are an emerging option. Only one non-randomized trial using bosentan or sildenafil with prostanoids has been published. It showed improvements of hemodynamics in the prostanoid/bosentan combination compared with prostanoid/placebo.

Other therapeutic options include heart/lung, double lung and single lung transplantations. Transplantation is indicated for non-responders to optimum medical therapy.

“Thanks to the intense, active collaboration of several centers, enough RCTs have been performed to give us some evidence to base guideline recommendations,” said Prof. Simonneau. “However, a lot remains to be done in long-range observational studies of novel therapies and combination
therapies.”

Assessment of Quality of Life in the Management of Pulmonary Arterial Hypertension

The VITAL (Quality of Lives Im-proved with Bosentan in Australian Open-Label) Study began in Australia during December 2001 to generate quality-of-life (QOL) data and to further study the efficacy of bosentan. This was an open-label, single arm study in patients with idiopathic PH or PAH associated with connective tissue disease. At the time of study inception, there was no readily available PAH-specific therapy. They looked at World Health Organi-zation (WHO) functional class, clinical worsening and QOL using the Short Form-36 (SF-36) Questionnaire. The 177 patients enrolled were followed for at least five months with a median follow-up of 9 months.

“We included the intent-to-treat data, last observed cases and the last observation carried forward using Kaplan-Meier analysis,” said Eli Gabbay, Clinical Associate Professor, Royal Perth Hospital, Perth, Western Australia “If you drop out of the study because of death or clinical deterioration, that score stays with you throughout the study. This is very important in QOL studies since failure to carry-forward results in QOL improvements solely related to sicker people dropping out.”

When the researchers viewed FC, over 90% of the patients stabilized or showed improvement. Of those in Class III, 50% improved and 45% remained the same with only a small number deteriorating. Those in Class IV showed little improvement (Keogh et al. 2004: manuscript in preparation).

“This result, yet again, shows that the earlier these patients are placed on bosentan, the better they do,” said Prof. Gabbay.

Overall survival also was consistent with the larger trials. At 300 days, there was a survival rate of almost 95%. There was a trend toward worse results from scleroderma patients, although small numbers made it hard to read too much into this statistic.

They used the SF-36 to assess QOL in this group.

“We asked the patients to report changes in how they feel in physical, social and emotional domains,” said Prof. Gabbay. “We also looked at body pain, general and mental health as well as vitality. The latter scores how much control over their lives they feel they have.”

At baseline, patients with WHO Class III or IV had a QOL score similar to that seen in other severe disease states. Treatment with bosentan improved scores in all parameters, except bodily pain, within 3 months. There was further improvement, excepting bodily pain, at six months of treatment. (Figure 1)

Physical functioning showed significant improvement at three months that continued to improve out to 6 months. There was a probable stabilization out to 12 months, although small numbers again made interpretation risky.

While all of this indicates there was a positive QOL change for the patient, how is this related to other surrogate parameters used to assess this disease? Prof. Gabbay has undertaken a small pilot study that suggested a correlation between QOL and functional parameters with a significant correlation between 6MWT and quality-of-life scores. However, if you look at change from baseline 6MWT and QOL, there doesn’t seem to be as close of a relationship, suggesting that they are probably measuring different things (Gabbay E et al. 2004: manuscript in preparation). (Table 1)

“This study indicates that the baseline quality-of-life in patients with Class III and IV PAH is comparable to other end stage diseases,” said Prof. Gabbay. “Treatment with bosentan significantly improved all PAH-relevant QOL measures and these effects increased with time.”

New Frontiers in the Treatment Strategies of Pulmonary Arterial Hypertension

DAlthough medications such as epoprostenol have improved survival, the future of PH treatment may be seen in novel targets for treatment and new methods of assessing outcomes.

“We start with a rapidly evolving understanding of the pathogenesis of PH,” said Lewis Rubin, M.D., Professor of Medicine, University of California, San Diego, La Jolla. “There are a number of new pathways that are just beginning to be unravelled.”

Angiopoietin is up-regulated in PH and may be an important signalling molecule for the bone morphogenic protein receptor (BMPR) pathway. Although mostly studied in familial PH, some possible ties with acquired forms of the disease are being noticed.

Both Endothelin-A and -B receptors may be important. It is not yet known whether selective or non-selective blockade of these receptors will be
superior.

“We also have potential targets of treatment in serotonin transport/receptor pathways, ion channels, and Vascular Endothelial Growth Factor (VEGF),” noted Dr. Rubin. “As we develop drugs to address these targets, either alone or in combination, we will explore ways to improve treatment strategies in pulmonary hypertension.”

He called for a reassessment of clinical endpoints used in treatment trials and incorporating some new measures. Included in his short list are BMP, troponin, endothelin and uric acid levels.

Another useful test may be cardiopulmonary stress testing. He finds stress hemodynamics to be especially interesting.

“We typically measure hemodynamics at rest, although our patients don’t lie flat on a cold, hard table for most of the day,” he noted. “Meaningful information on what happens to their pulmonary dynamics during physical activity should be useful.”

There are many non-invasive measurements that may be studied. Peak VO2 is an indicator of right ventricle status as is peak systolic blood pressure. Lower systolic blood pressure is an indicator of worse prognosis (Wensel R et al. Circulation. 2002;106:319).

“Until more data are available, I think cardiopulmonary exercise variables should be used as secondary endpoints,” said Dr. Rubin. “But they certainly do hold promise as non-invasive methods for us to use to follow patients.

Echo Doppler may also prove useful, especially in patients with PPH. Pericardial effusion is an ominous prognostic sign, probably indicative of elevated right atrial pressure with right ventricular failure. Right ventricular ejection time, as measured by the TI index or right mitral valve early filling may also be validated.
The health of the left ventricle is a possible indicator of right ventricle status. As the right side dilates, the left ventricle is compressed and underfilled.

Two recent studies, one with prostacyclin and the other with bosentan, looked at echocardiographic indices of pulmonary hypertension. In the placebo group, the ratio of right ventricle to left ventricle diastolic dimension continued to be enlarged. With bosentan, there was a decrease in right ventricular dimension, improvement in left-sided filling and a decrease in the ratio (Galie N et al. JACC. 2003;41:1380).

“Hemodynamics are important because PH is not simply pulmonary artery pressure,” stressed Dr. Rubin. “However, the correlation between clinical performance and hemodynamics is only fair, primarily because we have only sampled them at rest.”

Although rigorous trials have not been completed, there are some early signals that combination therapies may be beneficial. Hoeper and colleagues added bosentan to ongoing treatment with either inhaled iloprost or beraprost in an open, non-blinded study. The results indicate that adding bosentan produced substantial improvements in the 6MWT (Hoeper MM et al. Eur Resp J. 2003;22:330).